Tetrafluoroisopropylation of alkenes and alkynes enabled by photocatalytic consecutive difluoromethylation with CF2HSO2Na

Direct assembly of complex fluorinated motifs from simple fluorine sources is an attractive frontier of synthetic chemistry. Reported herein is an unconventional protocol for achieving tetrafluoroisopropylation by using commercially available CF2HSO2Na as a convenient source of the tetrafluoroisopropyl [(CF2H)2CH] group, which finds widespread applications in life science and material science. Visible-light-induced hydrotetrafluoroisopropylation of alkenes and carbotetrafluoroisopropylation of alkynes have been thus developed. Various structurally diverse α-tetrafluoroisopropyl carbonyls and cyclopentanones are selectively constructed under mild conditions. A photocatalytic triple difluoromethylation cascade, driven by consecutive reductive radical/polar crossover processes, leads to the direct assembly of a tetrafluoroisopropyl moiety from CF2HSO2Na. This C1-to-C3 fluoroalkylation protocol provides a practical strategy for the rapid construction of polyfluorinated compounds that are otherwise difficult to access, thus significantly enhancing the boundary of fluoroalkylation chemistry.

The incorporation of fluoroalkyl (R f ) moieties into organic compounds is a common and useful means to tune the physical, chemical, and biological properties, which are important for discovery of pharmaceuticals, agrochemicals, and advanced materials [1][2][3][4] .For example, the difluoromethyl (CF 2 H) group is a lipophilic H-bond donor and can be used as the biological isostere of a hydroxy, a thiol, and an amide 5,6 .Consequently, the past decades have witnessed a rapid development in the synthesis and application of difluoromethyl-containing molecules 7 .Among these, tetrafluoroisopropylated compounds [(CF 2 H) 2 CX (X = H, OH, halide, etc.)] are attracting more and more attention, because of their increased electron-withdrawing capability, hydrogen-bonding interaction, metabolic stability, and hydrophobicity enabled by the gem-difluoromethyl substitution [8][9][10][11][12] .Notable examples include the discovery of pesticide, protein stabilizer, ASH1L inhibitor, and potassium channel opener (Fig. 1a).Additionally, they have been widely used for the construction of functional materials 13 .More importantly, the two terminal C-H bonds in (CF 2 H) 2 CX provide more sites for biodegradation, which can avoid the health and environmental concerns about PFAS (per-and polyfluoroalkyl substances) 14 .Despite these intriguing applications, there is a dearth of methods for the efficient synthesis of tetrafluoroisopropyl motifs [15][16][17][18][19] .It was reported that the (CF 2 H) 2 CH group could be constructed via a Wittig reaction followed by hydrogenation (Fig. 1b) 15 , however, the use of highly volatile 1,1,3,3-tetrafluoroacetone (CF 2 HCOCF 2 H) has hindered its application.An alternative procedure relied on the electroreductive double hydrodifluoromethylation of terminal aryl alkynes with Hu reagent, 2-PySO 2 CF 2 H, which suffers from low yields and limited substrate scope 16 .Therefore, the development of efficient and general protocols for accessing tetrafluoroisopropylated compounds is still highly desirable.

Examination of substrate scope
With the optimized conditions established, the scope of this photocatalytic hydrotetrafluoroisopropylation reaction was investigated with a panel of functionalized alkenes, and the results are summarized in Fig. 2. Halogen atoms, such as fluorine (8 and 20), chlorine (9 and 21), and bromine (10), were well tolerated under standard conditions, providing opportunities for further functionalizations.Although slightly modified conditions, i.e., replacing LiOH with Cs 2 CO 3 , were required in some cases, both strong electron-donating groups like OMe (12) and electron-withdrawing groups, such as Ac ( 14), CF 3 (15), and CN ( 16), remained intact and produced α-tetrafluoroisopropyl esters in satisfactory yields.A methyl group at the para-and orthopositions of the aryl ring gave the desired products 18 and 19 in comparable yields (74% and 70%).Notably, a broad range of heteroaryls, namely 2,3-dihydrobenzofuran (22), dibenzo[b,d]furan (23), pyridine (24-26), benzo[d]thiazole (27), and thiophene (28), were all compatible.In addition to disubstituted alkenes, the reaction of trisubstituted olefins proceeded efficiently to furnish 29 and 30 in 65% and 75% yield, respectively.Variation of the R 3 group was then conducted.Alkenes activated by Ac, P(O)(OEt) 2 , and CN worked well for this hydrotetrafluoroisopropylation process (31-33), while the substitution with NO 2 and Bz was unsuccessful (34 and 35).In contrast, (E)ethyl 3-cyclohexylacrylate was an ineffective substrate, probably due to the absence of spin delocalization to aryl groups.Given the increasing importance of deuteriodifluoromethylated 48 compounds in pharmaceutical and agrochemical industries, we examined the feasibility of assembling a bis(deuteriodifluoromethyl) [(CF 2 D) 2 CD] unit from CF 2 DSO 2 Na (2b).To our delight, the reaction occurred smoothly to afford polydeuterated product 36 in 80% yield.The application of this method for late-stage elaboration of biologically active molecules was conducted as well.Highly functionalized alkenes, derived from ibuprofen (37), L-menthol (38), estrone (39), and empagliflozin (40), were successfully transformed to the corresponding αtetrafluoroisopropyl esters in moderate to high yields.
This visible-light-induced carbotetrafluoroisopropylation process appeared to be quite general.Various functional groups, such as F (43), Cl (44, 50, and 51), Br (45), OMe (46), CO 2 Et (47), CN (48), and OTBS (58), were accommodated to form the corresponding cyclopentanones in medium to excellent yields with exceptional diastereoselectivities.Substrates with pyridine and thiophene substituents worked   well in this reaction, producing 54 and 55 in good yields.The generation of spirocyclopentanones was feasible, as demonstrated by the efficient synthesis of 56 and 57.Gratifyingly, the reaction could be extended to the diastereoselective construction of synthetically challenging bicyclic framework 59, which bears four contiguous stereocenters.Alkyl ynones (R 1 = alkyl, not shown in Fig. 3) did not participate in this reaction, presumably due to the lack of spin delocalization to aryl groups.Likewise, this process was amenable to construct complex scaffolds stemmed from ibuprofen (60), clofibrate (61), amino acid (62), and estrone (63), making it an appealing protocol for the concise synthesis of biologically active compounds.

Mechanistic investigations
A set of control experiments were then performed to clarify the mechanism of this hydrotetrafluoroisopropylation process (Fig. 4).The model reaction was completely inhibited by the addition of 2,2,6,6-tetramethylpiperidinooxy (TEMPO), which is consistent with a radical pathway.In the presence of excess D 2 O (>98% D), [D 2 ]-3 was formed in 70% yield.Incorporation of 65% and 95% D at the αand β-carbon atoms, respectively, implies that carbanion formation is possible at these two positions.Under standard conditions, α-difluoromethyl ester 4, monofluoroalkene 6 55 , and difluoromethylated alkene 7 could be converted to the tetrafluoroisopropylated product 3 in high yields, supporting the involvement of these compounds as key reaction intermediates.
Based on these results, a possible mechanism for the alkene hydrotetrafluoroisopropylation, encompassing three consecutive photocatalytic cycles, is proposed in Fig. 5a, with 1a and 2a as representative substrates.In all the catalytic cycles, single electron transfer (SET) between the excited photocatalyst (PC*) and 2a produces •CF 2 H and a reduced photocatalyst (PC •− ).Spin delocalization to the benzene ring enables a regioselective addition of •CF 2 H to the α-carbon atom of 1a.Benzyl radical A is thus formed, which can be reduced by PC •− to yield benzyl carbanion B, thereby closing the first catalytic cycle.Driven by formation of a more stable carbanion, a formal 1,2-proton transfer (1,2-PT), probably via sequential protonation of the benzyl carbanion and basepromoted deprotonation at the α-position, transforms B to α-CF 2 H-substituted carbanion C. A rapid β-fluoride elimination 56,57 then generates monofluoroalkene 6.In the second photocatalytic cycle, addition of •CF 2 H to 6, and subsequent SET reduction and βfluoride elimination, produce difluoromethylated alkene 7. Formation of intermediates 6 and 7 could also be confirmed by HRMS analysis.In the third photoredox cycle, addition of •CF 2 H to 7 results in the generation of α-carbonyl radical F. A subsequent SET reduction by PC •− and protonation yield 3 as the final product.

Synthetic applications
The synthetic utility was investigated (Fig. 6).The photocatalytic hydrotetrafluoroisopropylation of 1zh proceeded efficiently to afford α-tetrafluoroisopropyl ester 64 in 71% yield.A subsequent hydrolysis furnished α-tetrafluoroisopropyl acid 65 in 95% yield.Given the significant bioactivity of its parent compound 66 68 , we evaluated the biological activity of compound 65.It did exhibit a potent peroxisome proliferators-activated receptor α (PPARα) transactivation activity (EC 50 = 4.2 μM), albeit with a lower activity than 66 (see Supplementary Fig. 6 in the Supplementary Information for details).

Discussion
In summary, visible light photocatalytic tetrafluoroisopropylations, including hydrotetrafluoroisopropylation of alkenes and carbotetrafluoroisopropylation of alkynes, are accomplished by using CF 2 HSO 2 Na as a precursor of the tetrafluoroisopropyl group.The reactions allow for facile, efficient, and highly selective construction of α-tetrafluoroisopropyl carbonyls and trans-α,β-disubstituted cyclopentanones from readily accessible starting materials.Mechanistic investigations indicate that the key to this C 1 -to-C 3 fluoroalkylation lies in three consecutive reductive radical/polar crossover processes trapped by two β-fluoride eliminations and one protonation.This radical assembly strategy opens up a pathway for the concise synthesis of complex fluorinated molecules that are difficult to obtain via traditional methods.We anticipate that direct assembly of other fluorinated and even non-fluorinated architectures via this strategy will be achieved in the near future.

Procedure for the photocatalytic hydrotetrafluoroisopropylation of alkenes
To a mixture of CF 2 HSO 2 Na (112 mg, 0.8 mmol), 4DPAIPN (15.9 mg, 0.02 mmol), H 2 O (36.0 mg, 2.0 mmol), and LiOH (19.2 mg, 0.8 mmol) in 2 mL of MeCN was added 1a (35.2 mg, 0.2 mmol) under a nitrogen atmosphere.After 24 h of irradiation at a distance of ~2 cm with 24 W of blue LEDs (PINO® lamps, 100% light intensity) at 25 °C, the reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated.The resulting residue was purified via column chromatography on silica gel to afford the desired product.

Procedure for the photocatalytic carbotetrafluoroisopropylation of alkynes
To a mixture of CF 2 HSO 2 Na (112 mg, 0.8 mmol), 4CzIPN (3.2 mg, 0.004 mmol) and Cs 2 CO 3 (130 mg, 0.4 mmol) in 2 mL of MeCN was added 41a (35.2 mg, 0.2 mmol) under a nitrogen atmosphere.After 18 h of irradiation at a distance of ~2 cm with 24 W of blue LEDs (PINO® lamps, 100% light intensity) at 25 °C, the reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated.The resulting residue was purified via column chromatography on silica gel to afford the desired product.

Evaluation of the PPARα transactivation activities
The transactivation activities on PPARα of compounds 65 and 66 were assessed using the Stop & Glo reagent, according to the manufacturer's instructions.HEK293 cells, purchased from American Type   Culture Collection (ATCC) with a catalog number of CRL-1573, were authenticated by Short Tandem Repeat test, then seeded into 96-well plates at a density of 8 × 10 4 cells/well in 90 µL of cell seeding medium (97% DMEM without phenol red, 2% charcoal stripped FBS and 1% GlutaMax) together with 10 µL transfection reagent (PPARα 1.079 mg/mL and pGL4.351.317 mg/mL).Compounds 65 and 66 were prepared 4-fold serial dilution with DMSO starting at 400 μM, 8 points in total, then transferred 500 nL to the compound plate using an Echo liquid handler.10-Fold dilutions of the compounds with 40 μL culture medium (88% DMEM with phenol red, 10% FBS, 1% P/S and 1% Gluta-Max) followed by transferring 10 μL to cell plates, which were placed in an incubator at 37 °C for 24 h.After removing 50 μL medium from each well, 50 μL luciferase assay reagent was added to the assay plate, followed by shaking at 25 °C for 20 min.The data were read on an Envision (Perkin Elemer: Envision 2105), then analyzed using XL-fit software (Supplier: ID Business Solutions Ltd., Software version: XL fit 5.0).Effect% = (Sample value-LC)/(HC-LC) × 100.

Reporting summary
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Fig. 1 |
Fig. 1 | Background and summary of this work.a Bioactive tetrafluoroisopropylated compounds.b Traditional routes to access the (CF 2 H) 2 CH group.c Tetrafluoroisopropylation via triple difluoromethylation with CF 2 HSO 2 Na.

Fig. 5 |
Fig. 5 | Proposed mechanism.a Pathway for the hydrotetrafluoroisopropylation of alkenes.b Pathway for the carbotetrafluoroisopropylation of alkynes.HRMS high resolution mass spectrometry.1st the first photocatalytic cycle.2nd the second photocatalytic cycle.3rd the third photocatalytic cycle.

Table 1 |
Optimization of reaction conditions